Functionalized nanoparticle formulations for oral drug delivery

Abstract

Drug delivery systems comprising binding partners conjugated to a nanoparticle encapsulating a therapeutic agent formulated for oral administration, and methods of delivering therapeutic agents across the gastrointestinal epithelium.

What is claimed is: 
     
         1 . A nanoparticle encapsulating a therapeutic agent that crosses an epithelial or endothelial barrier by transcytosis. 
     
     
         2 . The nanoparticle of  claim 1 , wherein the nanoparticle is conjugated with at least one FcRn binding partner. 
     
     
         3 . The nanoparticle of  claim 2 , wherein the at least one FcRn binding partner is covalently attached to the nanoparticle. 
     
     
         4 . The nanoparticle of  claim 2 , wherein the FcRn binding partner is non-covalently associated with the particle through any association selected from the group consisting of affinity interactions, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi stacking interactions, hydrogen bonding interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, and dipole-dipole interactions. 
     
     
         5 . The nanoparticle of any one of  claims 2 - 4 , wherein the FcRn binding partner comprises an IgG Fc fragment. 
     
     
         6 . The nanoparticle of any one of  claims 2 - 5 , wherein the FcRn binding partner allows the nanoparticle to bind to a complex comprising an FcRn receptor. 
     
     
         7 . The nanoparticle of  claim 6 , wherein the complex comprising an FcRn receptor is present in endothelial or epithelial cells. 
     
     
         8 . The nanoparticle of  claim 6 , wherein binding of the complex comprising an FcRn receptor allows the nanoparticle to cross a cell layer by transcytosis. 
     
     
         9 . The nanoparticle of  claim 6 , wherein binding of the complex comprising an FcRn receptor allows the nanoparticle to cross an epithelial or endothelial barrier by transcytosis. 
     
     
         10 . The nanoparticle of any one of  claims 1 - 9 , wherein the therapeutic agent is a diagnostic, prognostic, or prophylactic agent. 
     
     
         11 . The nanoparticle of any one of  claims 1 - 9 , wherein the therapeutic agent is selected from the group consisting of peptides, proteins hormones, cytokines, interferons, antibodies, antibody fragments, and enzymes. 
     
     
         12 . The nanoparticle of any one of  claims 1 - 9 , wherein the therapeutic agent is selected from the group consisting of anti-cancer and anti-bacterial agents. 
     
     
         13 . The nanoparticle of any one of  claims 1 - 9 , wherein the nanoparticle is suitable for oral administration. 
     
     
         14 . The nanoparticle of any one of  claims 1 - 13 , wherein the particle is an exosome. 
     
     
         15 . The nanoparticle of  claim 14 , wherein the exosome is isolated from bovine milk or colostrum. 
     
     
         16 . The nanoparticle of any one of  claims 1 - 13 , wherein the nanoparticle is a liposome, a lipoplex, a micelle, or a reverse micelle. 
     
     
         17 . The nanoparticle of any one of  claims 1 - 13 , wherein the nanoparticle is a polymeric nanoparticle. 
     
     
         18 . The particle of  claim 17 , wherein the polymeric nanoparticle comprises a polymer selected from the group consisting of polyalkylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polyfumarates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, poly(arylates), polycarbonates, polypropylene fumarates), polyhydroxyalkanoates, polyketals, polyesteramides, poly(dioxanones), polyhydroxybutyrates, polyhydroxyvalyrates, polyorthocarbonates, polyvinyl pyrrolidone), polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(methyl vinyl ether), and poly(maleic anhydride). 
     
     
         19 . The nanoparticle of any one of  claims 1 - 18 , wherein the nanoparticle is less than 1000 nm in diameter. 
     
     
         20 . The nanoparticle of any one of  claims 1 - 19 , wherein the nanoparticle comprises a targeting ligand that directs the nanoparticles to a systemic target. 
     
     
         21 . The nanoparticle of  claim 20 , wherein the targeting ligand is selected from the group consisting of selectins, integrins, immunoglobulins, cadherins, Arg-Gly-Asp (RGD), Asn-Gly-Arg (NGR), cyclic NGR, disulfide-based cyclic RGD (iRGD), Lyp-1, gastrin, bombesin, octreotide, epidermal growth factor (EGF), anti-EGFR antibody, vascular endothelial growth factor (VEGF), anti-VEGFR antibody, anti-HER2 antibody, hepatocyte growth factor receptor (HGFR), anti-HGFR antibody, tumor necrosis factor (TNF), or anti-TNF antibody. 
     
     
         22 . A composition comprising a nanoparticle of any one of  claims 1 - 21 . 
     
     
         23 . The composition of  claim 22 , formulated for oral administration to a mammalian subject. 
     
     
         24 . The composition of  claim 22  or  23 , comprising an external phase to the nanoparticles, wherein the external phase contains less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% unconjugated FcRn binding partners. 
     
     
         25 . The composition of any one of  claims 22 - 24 , comprising a liquid phase external to the nanoparticles, wherein the external phase contains less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% unencapsulated or unbound therapeutic agent(s). 
     
     
         26 . The composition of any one of  claims 22 - 25 , comprising a liquid phase external to the nanoparticles, wherein the external phase contains less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% protein. 
     
     
         27 . The composition of any one of  claims 22 - 26 , comprising a liquid phase external to the nanoparticles, wherein the external phase contains less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% Bovine Serum Albumin (BSA). 
     
     
         28 . The composition of any one of  claims 22 - 27 , comprising a liquid phase external to the nanoparticles, wherein the external phase contains less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% fats. 
     
     
         29 . The composition of any one of  claims 22 - 28 , comprising a solvent selected from n-methylpyrrolidone (NMP), an alcohol, or combinations thereof. 
     
     
         30 . The composition of any one of  claims 22 - 29 , wherein the pH of the external phase is between pH 4.5 and pH 6.5. 
     
     
         31 . A method of producing a therapeutic effect in a subject comprising orally administering a nanoparticle of any one of  claims 1 - 30  to the subject. 
     
     
         32 . A method of preparing a nanoparticle of  claim 1 , comprising:
 providing a nanoparticle comprising a therapeutic agent to be delivered encapsulated in a lipid or polymeric matrix; and,   conjugating at least one FcRn binding partner to a surface of the nanoparticle.   
     
     
         33 . A method of preparing a nanoparticle of  claim 1 , comprising:
 providing a nanoparticle conjugated to at least one FcRn binding partner on a surface of the nanoparticle; and,   loading a therapeutic agent into the nanoparticle.   
     
     
         34 . A method of preparing a nanoparticle formulation, comprising:
 isolating an exosome from bovine milk or colostrum;   purifying the exosome;   forming a composition comprising an external phase.   
     
     
         35 . The method of  claim 34 , wherein the isolating comprises at least one of centrifugation, filtration, size selection purification, and differential binding purification. 
     
     
         36 . The method of  claim 35 , wherein the size selection purification comprises size selection column purification. 
     
     
         37 . The method of  claim 35 , wherein the differential binding purification comprises selection by FcRn receptor binding. 
     
     
         38 . The method of  claim 35 , wherein the purifying comprises reducing any unconjugated FcRn binding partners to less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% in the external phase of the composition. 
     
     
         39 . The method of  claim 35 , wherein the purifying comprises reducing any unencapsulated or unbound therapeutic agent to less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% in the external phase of the composition. 
     
     
         40 . The method of  claim 35 , wherein the purifying comprises reducing any protein to less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% in the external phase of the composition. 
     
     
         41 . The method of  claim 35 , wherein the purifying comprises reducing any Bovine Serum Albumin to less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% in the external phase of the composition. 
     
     
         42 . The method of  claim 35 , wherein the purifying comprises reducing any fat to less than 10%, or less than 5%, or less than 2%, or less than 1%, or less than 0.1%, or less than 0.01% in the external phase of the composition. 
     
     
         43 . The method of  claim 35 , further comprising adjusting the pH of the external phase of the composition to a pH between pH 4.5 and pH 6.5. 
     
     
         44 . The method of  claim 35 , further comprising loading at least one therapeutic agent into the purified exosome. 
     
     
         45 . The method of  claim 44 , wherein the at least one therapeutic agent comprises a solvent selected from n-methylpyrrolidone (NMP), an alcohol, or combinations thereof. 
     
     
         46 . The method of  claim 46 , wherein the solvent comprises n-methylpyrrolidone (NMP). 
     
     
         47 . The method of any one of  claims 44 - 46 , wherein the at least one therapeutic agent is a chemotherapeutic agent. 
     
     
         48 . The method of  claim 47 , wherein the therapeutic agent is 7-Ethyl-10-hydroxycamptothecin (SN38).